RESUMO
Studying genetic determinants of intermediate phenotypes is a powerful tool to increase our understanding of genotype-phenotype correlations. Metabolic traits pertinent to the central nervous system (CNS) constitute a potentially informative target for genetic studies of intermediate phenotypes as their genetic underpinnings may elucidate etiological mechanisms. We therefore conducted a genome-wide association study (GWAS) of monoamine metabolite (MM) levels in cerebrospinal fluid (CSF) of 414 human subjects from the general population. In a linear model correcting for covariates, we identified one locus associated with MMs at a genome-wide significant level (standardized ß=0.32, P=4.92 × 10(-8)), located 20 kb from SSTR1, a gene involved with brain signal transduction and glutamate receptor signaling. By subsequent whole-genome expression quantitative trait locus (eQTL) analysis, we provide evidence that this variant controls expression of PDE9A (ß=0.21; P unadjusted=5.6 × 10(-7); P corrected=0.014), a gene previously implicated in monoaminergic transmission, major depressive disorder and antidepressant response. A post hoc analysis of loci significantly associated with psychiatric disorders suggested that genetic variation at CSMD1, a schizophrenia susceptibility locus, plays a role in the ratio between dopamine and serotonin metabolites in CSF. The presented DNA and mRNA analyses yielded genome-wide and suggestive associations in biologically plausible genes, two of which encode proteins involved with glutamate receptor functionality. These findings will hopefully contribute to an exploration of the functional impact of the highlighted genes on monoaminergic transmission and neuropsychiatric phenotypes.
Assuntos
Monoaminas Biogênicas/líquido cefalorraquidiano , Expressão Gênica , Estudo de Associação Genômica Ampla , Ácido Homovanílico/líquido cefalorraquidiano , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Metoxi-Hidroxifenilglicol/líquido cefalorraquidiano , 3',5'-AMP Cíclico Fosfodiesterases/genética , Adulto , Cromossomos Humanos Par 11 , Feminino , Loci Gênicos , Variação Genética , Técnicas de Genotipagem , Humanos , Modelos Lineares , Masculino , Proteínas de Membrana/genética , Transtornos Mentais/genética , Polimorfismo de Nucleotídeo Único , Proteínas Supressoras de TumorRESUMO
One hundred consecutive patients admitted to the hospital with the prospective diagnosis of appendicitis were evaluated retrospectively to determine the effect of the use of modern diagnostic techniques upon the accuracy of preoperative diagnosis. Appendectomy was performed on 48 patients. In three of these patients, the diagnostic process was assisted by the use of radiologic or ultrasound techniques. Of the 52 patients who did not undergo appendectomy, 13 patients clearly avoided surgery or were steered towards an other appropriate operative procedure due to findings on ultrasound or barium enema. Ultrasound was particularly useful in differentiating the etiology of right lower quadrant pain in the childbearing aged female. This study demonstrates that the traditionally expected 15% normal appendix rate can be narrowed (6.25% in this group of patients) without increasing morbidity, with the use of sophisticated diagnostic techniques in the evaluation of selected patients who present diagnostic dilemmas.